This program, which began more than 29 years ago, brings together investigators from multiple disciplines with an interest in the integrative aspects of circulatory function. Our major long-term goal has been to develop a quantitative analysis of circulatory dynamics and related control systems, including the kidneys, sympathetic nervous system, and endocrine systems. Two unique features of this program are: 1) it extensively utilizes mathematical systems analyses in conjunction with whole animal, cellular, and molecular experimentation to understand complex interactions between multiple components of cardiovascular diseases, such as hypertension and heart failure, are manifestations of abnormal control mechanisms that develop slowly over long periods of time. The research proposed in this application is described by the titles of the specific projects as follows: I. Neurohumoral and Renal Mechanisms of Hypertension; this project seeks to elucidate the mechanisms that contribute to the pathogenesis of obesity hypertension, which is of special relevance to human essential hypertension. II. Renal Control of Body Fluid Volumes and Circulatory Dynamics; this project will examine the role of endothelin, nitric oxide, and thromboxane in mediating impaired renal-pressure natriuresis and altered cardiovascular function in pregnancy-induced hypertension. III. Mechanisms of Salt-Sensitive Hypertension; this project will determine whether decreases in nitric oxide synthesis, particularly in the renal medulla, play a major role in salt-sensitive hypertension and the mechanisms involved. IV. Neural Mechanisms in Cardiorenal Regulation; this project will determine the role of the sympathetic nervous system in long-term regulation of renal function and arterial pressure, under normal conditions and in hypertension; V. Structural Vascular Adaptation of the Microcirculation; this project will determine the mechanisms that are involved in feedback regulation of angiogenesis, especially the role of the vascular endothelial growth factor. The total program project, including core support services, provides a unique interdisciplinary approach toward developing an integrative systems analysis of circulatory dynamics and their control.